The Xanthophyll Carotenoid Astaxanthin has Distinct Biological Effects to Prevent Ultraviolet Light-induced Cutaneous Inflammation, Abnormal Keratinization, Pigmentation and Wrinkling in a Reactive Oxygen Species-depletion Independent Fashion Even by Its Post-irradiation Treatment and Their Intracellular Signaling Mechanisms via the Mitogen and Stress-activated Protein Kinase 1

Exposure to ultraviolet (UV) radiation is the most harmful stimulus that deteriorates healthy human
skin. The cutaneous effects of UV mainly include acute inflammation (erythema/edema) and abnormal
keratinization in which prostaglandin E2, produced by cyclooxygenase (COX)-2, interleukin (IL)-8 and
a major keratinization regulatory factor transglutaminase 1 (TGase 1), respectively, play pivotal roles.
As a relatively late phase of UV-induced skin reactions, these effects also include hyperpigmentation,
wrinkle formation and skin carcinogenesis, the former two being associated with the UVB-induced
secretion or production of endothelin-1/stem cell factor and granulocyte macrophage colony
stimulatory factor (GM-CSF) by epidermal keratinocytes. Those factors then lead to an accentuated
expression of melanogenic key enzyme tyrosinase by epidermal melanocytes as well as an increased
expression of elastin degradable enzyme neprilysin by dermal fibroblasts in a paracrine fashion. Thus,
we characterized the biological effects of the xanthophyll carotenoid astaxanthin (AX) to prevent UVinduced
cutaneous inflammation, abnormal keratinization, pigmentation and wrinkling in a reactive
oxygen species depletion-independent manner even by its post-irradiation treatment. Then, we
determined the corresponding intracellular signaling mechanisms in human keratinocytes (HKs) and
human melanocytes (HMs). Thus, we clarified the intracellular stress signaling mechanism(s) involved
in the up-regulated gene expression of cycloxygenase (COX-2), interleukin (IL)-8, granulocyte
macrophage colony stimulatory factor (GM-CSF) and transglutaminase (TGase)1 in UVB-exposed
HKs as well as in the stimulated gene and/or protein expression of tyrosinases and microphthalmiaassociated
transcription factor (MITF) in stem cell factor (SCF)-treated HMs. Our results suggest that
the UVB-stimulated expression of COX-2, IL-8, GM-CSF and TGase1 is mediated predominantly via
the NFκB pathway and can be attenuated through a specific interruption of the
p38/MSK1/NFκBp65Ser276 axis and that SCF-stimulated melanogenesis can be abrogated by
interrupting MSK1 phosphorylation via the p38/MSK1/CREB/MITF axis. These findings provide new
evidence for the ROS depletion independent-signaling interruption by antioxidants.